GABAergic Mechanisms of Comorbid Alcohol and Nicotine Dependence

描述(由申请人提供)：酒精依赖和吸烟高度相关，然而研究潜在的神经化学的研究很少。在人类中，吸烟似乎调节了酒精依赖恢复期间GABAA-BZR的可获得性。临床数据表明，酒精依赖非吸烟者在急性戒断期间GABAA-BZR的可获得性增加，而酒精依赖吸烟者的GABAA-BZR活性受到抑制。此外，在长期戒酒期间，GABAA-BZR的可用性似乎有所下降；然而，这一点尚未得到系统研究。本项目的目的是使用[123I]碘马西尼和单光子发射计算机断层扫描(SPECT)来确定长期停用酒精和长期联合服用乙醇和尼古丁对大脑中GABAA-BZR的影响。我们还将检查同时戒酒和尼古丁期间GABAA-BZR的可用性变化，以及在尼古丁持续暴露的情况下戒酒时GABAA-BZR的变化，以及同时戒酒和吸烟与戒酒同时吸烟的人类GABAA-BZR的模型变化。我们将对50只青春期动物(每组10只)进行扫描。所有动物将在基线上接受2次扫描，例如，测试-重新测试。第1组给药24周，分别于停药1天、8天和12周进行显像。第2组为慢性尼古丁自我给药24周，停药1天、8天、12周后进行影像检查。3A组将自我给予酒精加尼古丁24周，并在停用酒精和尼古丁的第1天、第8天和第12周进行扫描。3B组将自我给予酒精加尼古丁24周，并将在戒酒1天、8天和12周时进行成像，但在此戒断期间将继续自我给予尼古丁。第4组为对照组，给予糖精治疗24周，停药后第1天、第8天、第12周进行扫描。将进行核磁共振扫描，以跟踪大脑灰质和白质以及脑脊液(CSF)的变化。我们假设：1)在急性酒精戒断期间，与基线和对照组相比，GABAA-BZR的可用性增加，而与酒精戒断12周的基线和对照组相比，GABAA-BZR的可用性降低；2)在尼古丁戒断期间，与基线或对照组相比，GABAA-BZR的可用性没有变化；以及，3)与单独使用乙醇相比，乙醇和尼古丁的组合将导致GABAA-BZR的可用性降低，即尼古丁将抑制乙醇诱导的增加，与同时从乙醇和尼古丁中戒断相比，退出乙醇将导致对增加的GABAA-BZR的更大的抑制。这项研究的发现将促进对酒精和尼古丁依赖高共患性背后的神经化学机制的理解，并将对吸烟者和非吸烟者的酒精依赖的治疗具有直接的临床意义。与公共健康相关：拟议的实验将通过描绘大脑机制GABAA-苯二氮卓类受体直接影响公共健康，该受体参与酒精依赖的恢复以及酒精依赖和吸烟的相互作用。这些研究将检查戒除酒精和尼古丁的情况，以确定这些药物对大脑化学的相互作用。这些研究最终将提供关于如何更成功地治疗这些代价高昂的成瘾的信息。

DESCRIPTION (provided by applicant): Alcohol dependence and tobacco smoking are highly associated, yet studies examining the underlying neurochemistry are scarce. In humans, tobacco smoking appears to regulate the availability of the GABAA- BZR during the recovery from alcohol dependence. Clinical data suggest increased GABAA-BZR availability in alcohol dependent nonsmokers during acute withdrawal that is suppressed in alcohol dependent smokers. Additionally, there appears to be decreased GABAA-BZR availability during prolonged alcohol withdrawal; yet this has not been systematically studied. The purpose of this project is to determine the effects of withdrawal from chronic orally-delivered ethanol versus chronic co-administration of ethanol and nicotine on the GABAA- BZR in brain over time using [123I]iomazenil and single photon emission computed tomography (SPECT). We will also examine changes in GABAA-BZR availability during withdrawal from both ethanol and nicotine simultaneously, versus withdrawal from ethanol in the presence of continued nicotine exposure to model changes in GABAA-BZR in humans that quit drinking and smoking simultaneously vs. quitting drinking while continuing to smoke. We will obtain scans in 50 adolescent animals (n=10 per group). All animals will receive 2 scans at baseline, e.g., test-retest. Group 1 will self-administer chronic ethanol for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 2 will self-administer chronic nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 3A will self-administer ethanol plus nicotine for 24 weeks and will be scanned at 1 day, 8 days and 12 weeks withdrawal from both ethanol and nicotine. Group 3B will self-administer ethanol plus nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal from ethanol, but will continue to self-administer nicotine during this withdrawal period. Group 4, a control condition, will self-administer saccharin for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks after termination of saccharin. MRI scans will be obtained to track changes in brain gray and white matter and cerebrospinal fluid (CSF). We hypothesize that there will be 1) increased GABAA-BZR availability compared to baseline and controls during acute ethanol withdrawal and decreased GABAA-BZR availability compared to baseline and controls at 12 weeks ethanol withdrawal; 2) no change in GABAA-BZR availability compared to baseline or controls during nicotine withdrawal; and, 3) the combination of ethanol and nicotine will result in decreased GABAA-BZR availability compared to ethanol alone, i.e., nicotine will suppress the ethanol-induced increase, and withdrawal from ethanol into the presence of nicotine will result in a greater suppression of increased GABAA-BZR availability compared to withdrawal from ethanol and nicotine simultaneously. The findings from this study will advance the understanding of the neurochemical mechanisms that underlie the high comorbidity of alcohol and nicotine dependence and will have direct clinical implications for the treatment of alcohol dependence in both smokers and nonsmokers. PUBLIC HEALTH RELEVANCE: The proposed experiments will directly impact public health by delineating a brain mechanism, the GABAA- benzodiazepine receptor, which is involved in the recovery from alcohol dependence and in the interaction of alcohol dependence and tobacco smoking. These studies will examine the withdrawal from both alcohol and nicotine to determine the interaction of these drugs on brain chemistry. These studies will ultimately provide information on how to more successfully treat these costly addictions.